Variations in two genes related to inflammation may be a major risk factor for developing lung cancer, according to a team of scientists from the National Cancer Institute and the University of Texas M. D. Anderson Cancer Center. The effect of these genes is especially strong among heavy smokers, suggesting that the inflammatory response is important in modulating the damage caused by tobacco smoke.

'Besieged Environment' Created

Their study, published in the July 1 issue of Cancer Research, is the first to pinpoint the mechanism by which damage to the lung might trigger an overzealous inflammatory response by the immune system, leading to lung cancer. The variants, or polymorphisms, were found in genes for interleukin (IL)1A and IL1B, two signaling molecules that immune system cells secrete in response to infection or tissue damage.

"Our findings help explain how heavy smoking, for example, combines with a genetic predisposition to create a besieged environment within the lungs," said lead author Eric Engels, MD, MPH, researcher at the Viral Epidemiology Branch of the NCI's Division of Cancer Epidemiology and Genetics. "Essentially, sustained inflammation alters the microenvironment of the lung tissue, damaging cells and altering DNA."

Inflammation is part of the immune system's arsenal to combat the effects of infection and cell damage. However, prolonged or intense inflammation could lead to conditions within the lung environment that foster cancer, Engels said. Previous studies have shown that diseases associated with lung damage, such as tuberculosis and asthma, increase the risk of developing lung cancer. Likewise, exposure to tissue-damaging substances like silica and asbestos, inhaled into the lungs, has also been shown to increases lung cancer risk.

Chemical Cascade

"Inflammation has long been thought to be a factor in many cancers, including lung cancer, and could provide an explanation how damage to lung tissue leads to cancer," Engels said. "Knowing more about the downstream effects of these polymorphisms, and discovering others like them, will increase our understanding of how some people are predisposed to developing cancer."

The researchers compared differences in genes related to inflammation between more than 1,500 lung cancer patients and 1,700 controls at M. D. Anderson Cancer Center. More than 80% of the cancer patients in the study were current or former smokers. Among the 59 variations in 37 inflammation-related genes studied, the researchers discovered that some variants in the genes for IL1A and 1B, are found more frequently in patients with lung cancer—and especially among heavy smokers. The effect was most profound in polymorphisms in IL1B, which is central to the inflammation process, the researchers said.

According to Engels, the IL1B protein is an integral part of the chemical cascade by which cell signals moderate the response to inflammation. Variations in the gene may lead to greater expression of the protein, which is more likely to turn on the cascade and sustain the damaging effects of inflammation. Over time, the constant damage of inflammation could lead to genetic damage and cancer, Engels said.